In acute promyelocytic leukemia (APL), the t(15;17) translocation fuses a nuclear receptor, RARα, to a nuclear matrix protein, PML (de Thé, et al. (1991) Cell 66:675-684). Transgenic mice expressing PML/RARα show impaired neutrophilic differentiation and develop leukemia, demonstrating that expression of the fusion protein initiates this malignancy (Brown, et al. (1997) Proc. Natl. Acad. Sci. USA 94:2551-2556). PML/RARα impairs both nuclear receptor-induced differentiation and PML-triggered apoptosis, likely accounting for the differentiation block and the unrestrained growth of the leukemic cells (Quignon, et al. (1997) Biochim. Biophys. Acta 1333:M53-M61; Lallemand-Breitenbach, et al. (1999) J. Exp. Med. 189:1043-1052). Expression of PML/RARα leads to accumulation in affected cases of immature promyelocytes in the bone marrow and peripheral blood. Inhibition of the retinoic acid response appears to involve the stabilization of corepressor proteins-histone deacetylase complexes on retinoic acid response elements (Lin, et al. (1998) Nature (London) 391:811-814; Grignani, et al. (1998) Nature (London) 391:815-818; He, et al. (1998) Nat. Genet. 18:126-135; Guidez, et al. (1998) Blood 91:2634-2642). The PML protein, which is localized on nuclear subdomains (PML nuclear bodies), has growth-suppressive and proapoptotic properties (Koken, et al. (1994) EMBO J. 13:1073-1083; Dyck, et al. (1994) Cell 76:333-343; Weis, et al. (1994) Cell 76:345-356; Mu, et al. (1994) Mol. Cell. Biol. 14:6858-6867; Quignon, et al. (1998) Nat. Genet. 20:259-265; Wang, et al. (1998) Nat. Genet. 20:266-272; Daniel, et al. (1993) Blood 82:1858-1867; Koken, et al. (1995) Oncogene 10:1315-1324). PML/RARα expression delocalizes nuclear body proteins, which has been proposed to account for apoptosis resistance (Grignani, et al. (1993) Cell 74:423-431).
Retinoic acid promotes differentiation of APL cells, causing degradation of PML/RARα and inducing clinical remissions in patients (Huang, et al. (1988) Blood 72:567-572). Degradation of PML/RARα after retinoic acid-treatment occurs through proteasome—as well as caspase-dependent pathways (Zhu, et al. (1999) Proc. Natl. Acad. Sci. USA 96:14807-14812). Arsenic trioxide also induces remissions, through combined induction of apoptosis and differentiation (Chen, et al. (1996) Blood 88:1052-1061). Both retinoic acid and arsenic trioxide treatments trigger PML/RARα degradation and nuclear body restoration (Zhu, et al. (1997) Proc. Natl. Acad. Sci. USA 94:3978-3983; Yoshida, et al. (1996) Cancer Res. 56:2945-2948; Muller, et al. (1998) EMBO J. 17:61-70; Raelson, et al. (1996) Blood 88:2826-2832), suggesting that the therapeutic action of these two drugs could be due to the down-regulation of the oncogenic fusion protein. However, data to support this hypothesis are conflicting (Nervi, et al. (1998) Blood 92:2244-2251; Fanelli, et al. (1999) Blood 93:1477-1481). Retinoic acid resistant, APL cases can occur and the trivalent form of arsenic has been used successfully in the treatment of these cases. It has been suggested that PML/RARα degradation is most likely responsible for the cross-facilitation of retinoic acid and arsenic trioxide effects (Lallemand-Breitenbach, et al. (1999) supra; Gianni, et al. (1998) Blood 91:4300-4310).
U.S. patent application Ser. No. 10/056,666 teaches compounds and methods of use thereof for modulating lysosome function wherein the compounds enhance the enzymatic capacity of lysosomes to suppress neuropathogenesis.